Genetic analysis is a proven tool for determining the genetic contribution to a disease. However, many methods have the disadvantage of being very complex, and of having some fundamental parameters that can be tested only with difficulty. Also, there only are there limited number of modes of inheritance that we know how to test and, as more complex diseases are investigated, the problem of heterogeneity looms ever larger. In the previous grant period, we 1) developed and tested a two- locus segregation analysis method; 2) developed a segregation- analysis-based method for looking at heterogeneity; and 3) showed that one can reject a recessive mode of inheritance at the HLA locus for type 1 diabetes (IDDM), but cannot reject a 3-allele model. This proposal has two broad goals: I) To develop relatively simple and robust methods for genetic analysis, especially two-locus analysis, heterogeneity testing, and ascertainment bias correction; II) to test these and other fundamental assumptions of genetic analysis. We will approach both of these goals using computer simulation as a primary tool. Under goal #I, we propose to: A. Continue development of two-locus segregation analysis; B. Develop and test a segregation analysis-based method for the detection of heterogeneity in disease and as a tool for generating testable heterogeneity hypotheses; C. Investigate in detail the antigen-frequency-among-affected method for testing the mode of inheritance in HLA-related diseases. D. Develop a proposed method for ascertainment bias correction when the standard method cannot be used. Under goal #II, we will: A. Test the assumptions of standard ascertainment bias correction and assess the effect on genetic parameter estimation; B. Quantitate the bias that can arise from sampling in pedigree data; C. Investigate the amount of information contained in a genetic data set and the implications for genetic methodologies of the limits of that information. We will use the methods developed to examine the mode of inheritance of, and heterogeneity in, three diseases: IDDM, coeliac disease, and cleft-lip+palate.